166Ho-DOTMP Skeletal
Targeted Radiotherapy (STRTM)
with Melphalan and Autologous
Stem Cell Support for Multiple
Myeloma
Bensinger W, Giralt S, Goodman M,
Salzman D, Ruffner K, Breitz H.
Fred Hutchinson Cancer Research Center, Seattle, WA , M.D. Anderson Cancer
Center, Houston TX, U. Miami Miami, FL,
U. Alabama, Birmingham AL, Vanderbilt University, Nashville TN, NeoRx Corp,
Seattle WA
Abstract
Background: 166Ho-DOTMP is a radiotherapeutic that localizes
specifically to the skeleton and can deliver high dose radiation
to
the bone and bone marrow for skeletal targeted radiotherapy
(STR). Follow -up data from 3 clinical trials of patients with multiple
myeloma are presented.
Methods: In 2 Phase I/II dose -escalation trials, 82 patients received
a dose of 166Ho-DOTMP calculated to deliver 20, 30, or 40
Gy to
the red marrow, plus melphalan ( mel; 140 or 200 mg/m 2) +/- 8 Gy
TBI, followed by autologous stem cell transplant (PBSCT). As of
12/1/03, all subjects have been followed for at least 38 months.
In
a separate Phase II dosimetry trial, 12 patients received 2 trac
er
doses of 166Ho-DOTMP to determine the reproducibility of
biodistribution and pharmacokinetics (PK), followed by a 25
Gy
therapy dose with continuous bladder irrigation, followed by
200 mg/m 2 mel and PBSCT. These patients have been followed
for at least 17 months.
Results: Up to 2.3 Ci/m2 166Ho-DOTMP was given in the Phase I/II
trials. 29/82 (35%) patients achieved complete response (CR)
and ORR (CR + PR + SD) was 91% (7 pts not evaluable). Median
duration of CR was > 24 months, and the Kaplan-Meyer estimate
of 3 year survival was 60% for all 82 patients. In the 10 patients
who received 750 mCi/m2 +/-10%, the CR rate was 40% and the
3-year survival was 90%. However, dose-related radiation-induced
bladder and kidney toxicity appeared between 3 and 13 months
post-therapy at high doses. Currently, 17 months of follow-up
from the Phase II dosimetry trial shows no occurrence of
hemorrhagic cystitis or elevated creatinine > Grade 2. The dose
of 166Ho-DOTMP in this study was 550 to 860 mCi/m2. A CR rate
of 17% was seen, and the biodistribution and PK of 166Ho-DOTMP
were reproducible. Monitoring for safety and duration of response
is ongoing for both trials.
Conclusions: Follow-up from the Phase II dosimetry trial confirms
that 750 mCi/m2 +/- 10% of 166Ho-DOTMP provides favorable
efficacy and safety as part of the conditioning regimen for patients
with multiple myeloma undergoing autologous PBSCT. A Phase
III, multicenter, randomized trial with 750 mCi/m2 166Ho-DOTMP is
planned to begin enrollment in Q1 of 2004.
STR: Skeletal Targeted
Radiotherapy with 166Ho-DOTMP
· Delivery of radiation to the bone and bone
marrow by specifically targeting beta-emitting
radioisotopes to the skeleton
· Beta emitting radioisotopes deposit radiation
within a few mm from where they decay, the
distance depends on the energy of the beta
emitter
166Holmium (166Ho)-DOTMP
· 166Ho is a high energy beta emitter depositing 90% of its
energy over 4 mm
·T
= 27 hours, short enough to allow safe PBSC infusion
1/2
within 6-7days
· 166Ho emits gamma photons suitable for imaging by
gamma camera
· 1,4,7,10 tetraazacycloDodecane-1,4,7,10-
TetraMethylene-Phosphonate, DOTMP is a
tetraphosphonate chelate that localizes in bone matrix by
binding to calcium
· Increased bone turnover causes increased localization
4 hours after injection
· Anterior and posterior
whole body gamma
camera images
· Rapidly targets bone
surfaces and delivers
radiation to bone and
marrow
· Unbound 166Ho-
DOTMP rapidly
excreted via urinary
tract
Phase I/II Studies
·
Dose escalation of 166Ho-DOTMP in 88 patients
·
Target marrow radiation dose of 20, 30 or 40 Gy from 166Ho-
DOTMP in combination with 140 mg/m2 melphalan, 140 mg/m2
melphalan + 8 Gy TBI or 200 mg/m2 melphalan
·
460 ­ 4700 mCi 166Ho-DOTMP administered
·
Excellent acute safety profile
·
Dose limiting toxicity from late radiation to urinary tract
­ Hemorrhagic cystitis in absence of bladder irrigation at high dose
­ Kidney toxicity at high dose of 166Ho-DOTMP
·
Efficacy: Overall 35% CR
·
Three year survival: Overall 60%
Incidence TTP/HUS by
166Ho-DOTMP Dose Administered
Dose
<552
552-675
675-825
825-1008
1008-1232
>1232
(mCi/m2)
(n=7)
(n=8)
(n=10)
(n=16)
(n=13)
(n=29)
No.
0
0
0
1
0
6
· TTP/HUS presented 6-13 months post treatment
· Biopsy findings consistent with TMA
Incidence Late Renal Toxicity
(NCI Grade 3&4) by 166Ho-DOTMP
Dose Administered
Dose
<552
552-675
675-825
825-1008
1008-1232
>1232
(mCi/m2)
(n=7)
(n=8)
(n=10)
(n=16)
(n=13)
(n=29)
Grade 3-4
0
1
0
2
1
17
renal tox
(0%)
(12.5%)
(0%)
(12.5%)
(7.7%)
(59%)
Grade 4
0
0
0
1
1
11
renal tox
(0%)
(0%)
(0%)
(6.3%)
(7.7%)
(38%)
· Grade 3-4 elevated creatinine in 24% of all patients
· Majority seen at higher 166Ho-DOTMP doses
Efficacy: CR and 3-yr Survival
by 166Ho-DOTMP Dose Administered
Dose
<552
552-675
675-825
825-1008
1008-1232
>1232
(mCi/m2)
(n=7)
(n=8)
(n=10)
(n=16)
(n=13)
(n=29)
CR
1
2
4
6
4
12
(14.3%)
(25%)
(40%)
(37.5%)
(30.8%)
(41.4%)
3-yr
survival
(57%)
(50%)
(90%)
(63%)
(69%)
(45%)
Phase II Dosimetry Study
· Designed to deliver 25 Gy marrow dose if skeletal
localization adequate
· Variable skeletal uptake, 19% - 39%
· To deliver 25 Gy, 551-860 mCi/m2 or 1014 to 1776 mCi
166Ho-DOTMP administered, followed by melphalan 200
mg/m2 and PBSCT
· All pts underwent bladder irrigation for 6 hours following
with therapy dose
· PK and imaging showed consistent intra-patient
biodistribution with two tracers and a therapy dose
Safety: Dosimetry Study
· Follow-up 17 to 22 months
· Marrow engraftment within 15 days (9-15 ANC,
6-15 platelets) in all 12 patients
· SAEs: Not related to STR
­ Fever = 6 (5 normal ANC; 1 neutropenic), variety of infectious
causes, typical of this patient population
­ 1 death from septic and cardiogenic shock at 6 months
­ Autologous GVHD = 1
· Possibly related
­ 1 grade 2 creatinine in patient with H/T and diabetes
· No hemorrhagic cystitis
· No TTP/HUS nor > Grade 3 serum creatinine
Summary: Dosimetry Study
(n=12)
166Ho DOTMP Dose (mCi/m2)
550-860
Hemorrhagic Cystitis
0
Grade 3-4 creatinine
0
TTP/HUS
0
CR rate
17%
1-yr survival
92%
Phase III STR Protocol
A randomized, multi-center study comparing
the safety and efficacy of 166Ho-DOTMP plus
melphalan to melphalan alone as conditioning
for autologous PBSCT in patients with primary
refractory multiple myeloma
Rationale of Complete Response as Endpoint:
Survival of Patients with MM treated with
166Ho-DOTMP + Mel + PBSC
Based on Complete Response to Transplant
1
0.8
CR n=29
al 0.6
ivv
0.4
Sur
<CR n=54
0.2
0
01
2
3
4
5
6
Years
Rationale for Dosage:
750 mCi/m 2 166Ho-DOTMP
· Long-term follow -up of the 10 patients who
received between 675 and 825 mCi/m 2,
(750 mCi/m 2 + 10%) showed
­ No cases of TTP
­ No Grade 4 renal toxicity
­ CR rate was 40%
­ 2-year survival was 100%
­ 3-year survival was 90%
2 of these patients are nearly 5 years post -treatment
4 additional patients nearly 4 years post treatment
Survival of Patients with MM treated with
166Ho-DOTMP + Mel +/- TBI + Autologous PBSC
Based on Dose (mCi/bsa)
1
0.8
750/m2
1100/m 2
900/m 2
al 0.6
ivv
600/m 2
0.4
Sur
1200/m 2
500/m 2
0.2
N=83
0
0
12
3
4
5
6
Years
Rationale for Refractory
Disease
·
22 subjects with primary refractory disease in Phase I/II trials
·
Response rates compare favorably with other studies of
AHSCT in primary refractory subjects
·
ABMTR data CRR 7%
·
CR rate = 23%; PR = 45%; OR = 68%
·
Three year survival in all PRD pts with 166Ho-DOTMP was
41% (n=22)
·
Three year survival in pts with 200 mg/m2 + 166Ho-DOTMP
was 63% (n=8)
·
No previous randomized studies
Phase III Objectives
· Primary objective
­ To determine the efficacy comparing 166Ho-DOMTP +
chemotherapy + transplant vs chemotherapy + transplant
alone
· Secondary objectives
­ Compare survival and progression-free survival
­ Compare overall response rate (CR+VGPR+PR), best
response within 6 months, and duration of response
­ Compare the safety profile
­ Assess the biodistribution and estimated radiation absorbed
dose to kidney in the first 20 subjects
Enrollment
Not qualified,
Tracer Dose
insufficient or
abnormal uptake
30 mCi 166Ho-DOTMP
Qualifies
Patient off study
(28 days follow-up)
Randomization
or
A
Arm
Arm
B
Therapeutic Dose
of 750 mCi/m2
166Ho-DOTMP
200 mg/m2
200 mg/m2
Melphalan
Melphalan
PBSC Transplant
Efficacy evaluations for 3 years
Safety followed for 10 years
Phase III Investigational Plan
· 240 subjects with primary refractory multiple myeloma
eligible for transplant
· ~40 clinical sites
· Pts to have failed prior high dose steroid therapy and be
within 18 months since induction therapy
· 1:1 randomization: 200 mg/m 2 melphalan alone or 200
mg/m 2 melphalan + 750 mCi/m 2166Ho-DOTMP
· All patients to receive continuous bladder irrigation for 6
hours
· Primary efficacy: CR at 6 months post transplant
· Safety follow up for 10 years
· Study now open for enrollment in US

Document Outline